Furans and method of preparation



Patented June 9, 1953 UNITED STATES PATENT OFFICE 2,641,601 v FURANS AND METHOD or PREPARATION Moses Wolf Goldberg, Upper Montclair, and Albert Israel Rachlin, Maywood, N. J assignors .to Hofimann-La Roche Inc., Nutley, N. .L, a corporation of New Jersey No Drawing. Application November 24, 1950, .Serial No. 197,492

dihydro 2 imidazolyl .and dialkylaminoalkylcarbamyl radicals. The invention also encompasses the salts of the aforesaid compounds with acids, and the method for preparingsuch compounds. The new compounds are useful as antifungal and antitrichomonas compounds.

The new compounds can be designated as 2- (X-phenyl) 5 (Xi-phenybfurans and 2-(X- phenyl) -5- (X1-pheny1) monochlorofurans,wherein X and X1 represent hydrogen, guanyl, 4,5-di hydro-Z-imidazoly'l, or dialkylaminoalkylcarbamyl radicals, at least one of X and Xrbeing one of the last three mentioned substituents. 2- phenyl-5-(X1-phenyl)furans disclosed herein in which X1 represents 4,5-dihydro-2-imidazolyl are claimed in continuation-impart application Serial No. 269,618, filed February 1, ,1952.

In general, the 2,5-diphenyl-monochlorofurans which have a guanyl or 4,5-dihydr.o 2-imidazolyl radical attached to at least one of the phenyls,

can be prepared in the following manner: Anv

acetophenone is condensed with a phenylglyoxal, at least one of these reagents containing a nuclear attached cyano radical, to form a l-lR- benzoyl)-'2-'(R1-'benzoyl) ethylene which can be represented by the formula:

wherein R and R1 represent. hydrogen and'cyano,

A1k 1-0 t=NH-Ho1 at least one of R2 andRa being such a radical. The latter compound is reacted with ammonia or ethylene diamine to produce the corresponding 2,5-diphenyl-monochlor,ofurans wherein at least one of the phenyls has attached thereto a guanyl or 4,5-dihydro-2-imidazolyl radical.

The 2,5-diphenyl-furans which have a guanyl or 4,5-dihydro-2-imidazolyl radical attached to at least one of the phenyls can be prepared-as follows: The cyano-substituted dibenzoyl-ethylenes are treated with stannous chloride in the presence of concentrated hydrochloricand glacial ing as defined hereinabove.

acetic acid, to form 2-(R -phenyl)-5-(R1-phenyllfurans wherein R and R1 have the same mean- The thus formed cyano-substituted 2,5-diphenyl-furans are then reacted with a lower alkanol and hydrogen chloride to produce 'Z-(Rz-phenyI)-5-(R3-phenyl)- furans wherein R2 andrRa have the same meaning as hereinabove defined. The thus formed 2,5-diphenyl-furan lower alkyl imidic ester hydrochlorides .are reacted with ammonia .or ethylene diamine to produce the corresponding .guanyl and 4,5-dihydro-2-imidazolyl-substituted 2,5-diphenyl-furans.

The 2,5-diphenylemonochlorofurans and :the

'2,'5-diphenyl-furans wherein at least one of the,

phenyls has attached thereto a dialkylaminoalkylcarbamyl radical can beproduced in the following manner: The lower alkyl imidic ester hydrochlorides of the 2,5-diphenyl-nonochlorofurans or of the 2,5-diphenyl-furans are reacted with water, whereupon the corresponding car- 'boxylic esters are obtained which upon saponifiication yield the corresponding carboxy compounds. The latter can be converted, for example, byrea-ction with a .thionyl halide, to the The 1carboxyliccorresponding carbonyl halides. esters as well as the carbonyl'halides upon treatment with a dialkylaminoalkylamine, such as B- diethylaminoethylamine, yield the corresponding 2,5-diphenyl-monochlorofurans and the 2,5-di phenyl-furans wherein at least one of the phenyls has attached thereto .a dialkylaminoalkylcarbamyl radical. I

Accordingly, in its broadaspects, the invention comprises converting cyano-substituted diben- 'zoyl-ethylenes into lower alkyl imidic ester hy- :glyoxal, rather than a cyanoacetophenone with phenylglyoxal, since better yields are obtained with the first mentioned reaction. Phenylglyoxal and cyano substituted phenylglyoxal are obtained by oxidizing acetophenone and cyano substituted acetophenones, respectively, with selenium dioxide. 7 v

3 The preparation of those starting materials, which are new, is illustrated by the following examples:

EXAMPLE A p-Cyanophenylglyomal To a mixture of 500 cc. of dioxane and 20 cc. of water were added 56 grams of finely divided selenium dioxide. The mixture was stirred at 50 C. until the selenium dioxide had dissolved, and then 72.5 grams of p-cyanoacetophenone were added. The mixture was refluxed with stirring for 6 hours, during which time black metallic selenium precipitated. Stirring was continued without heating for 18 hours, and then the selenium was removed by filtration. The solvent was removed in vacuo and the hot residue was dissolved in 300 cc. of acetone. The acetone was flashed off and the residue was distilled on an oil bath. The p-cyanophenylglyoxal was obtained as a heavy, viscous oil boiling at 104-110 C./l.5 m. A sample of the oily material was converted to the hydrate by trituration with water. After several crystallizations from nitromethane, the white crystalline p-cyanophenylglyoxal hydrate melted at 96-100 C.

EXAMPLE B m-Cyanophenylglyowal To a mixture of 500 cc. of dioxane and 20 cc. of water were added 56 grams of finely divided selenium dioxide. The mixture was stirred at 50 C. until the selenium dioxide had dissolved, and then 72.5 grams of m-cyanoacetophenone were added. The mixture was refluxed with stirring for 6 hours, during which time black metallic selenium precipitated. Stirring was continued without heatin for 18 hours, and then the selenium was removed by filtration through a thin pad or" activated charcoal. The solvent was removed in vacuo, and the hot residue was dissolved in 300 cc. of acetone. The acetone was flashed OE and the residue was distilled on an oil bath. A heavy viscous oil boiling at 123-126" C. at 0.3 mm. was obtained. The hydrate prepared by treating the glyoxal with water was a white solid which melted at 54-57 C.

EXAMPLE C 1,2-bis (go-cyanobenzoyl) ethylene A mixture of 43.4 grams of p-cyanophenylglyoxal, 39.6 grams of p-cyanoacetophenone, and 31 cc. of acetic anhydride was heated for 6 hours in an oil bath at 140-150 C. A product started to crystallize from the hot reaction mixture after 1 hour. The mixture was allowed to stand at room temperature for 18 hours. The cake was broken up, the solid matter was collected on a suction filter, and washed with 50 cc. of glacial acetic acid. The product was purified by recrystallization from nitrobenzene to give 1,2-bis(pcyanobenzoybethylene as yellow-orange needles, M. P. 261-262 C.

EXAMPLE D 1,2-bis (wt-cyanobenzoyl) ethylene A mixture of 79 grams of m-cyanophenylglyoxal, '72 grams of m-cyanoacetophenone, and 56 cc. of acetic anhydride was heated for 6 hours in an oil bath at 145-152 C. The mixture was then allowed to' stand at room temperature for 18 hours. The cake was triturated with 25 cc. of glacial acetic acid, filtered, and washed on the filter with 75 cc. of glacial acetic acid, 100 cc.

of absolute ethanol, and cc. of ether. The crude yellow solid obtained was recrystallized from 2'70 cc. of nitrobenzene yielding 1,2-bis(mcyanobenzoyl) ethylene, M. P. 250-252 C., in the form of yellow crystals.

EXAMPLE E' 1 (in-cyanobenzoyl) -2- n-cyanobenzoyl) ethylene (1). A mixture of 3.54 grams of p-cyanophenylglyoxal hydrate, 2.9 grams of m-cyanoacetophenone, and 4.7 cc. of acetic anhydride was heated for 2.5 hours in an oil bath at 145-150 C. The mixture was allowed to cool to room temperature and washed'with 20 cc. of glacial acetic acid, yielding 1 (m cyanobenzoyl) 2 (p cyanobenzoyDethylene, M. P. 230-234 C.

(2) A mixture of 33.2 grams of m-cyanophenylglyoxal, 30.4 grams of p-cyanoacetophenone, and 24 cc. of acetic anhydride was heated for 2.5 hours in an oil bath at -150 C. Vacuum was applied to the hot mixture while cooling. After standing for 48 hours, the product was triturated with 25 cc. of acetic acid, filtered, washed with 50 cc. of acetic acid, and air dried. The yellow solid was recrystallized from 250 cc. of nitrobenzene yielding l-(m-eyanobenzoyl)-2- (p-cyanobenzoyl) ethylene, M. P. 234-236 C.

EXAMPLE F 1 -ben2oyZ-2- a-cyanobenzoyl) ethylene (1) A mixture of 79.4 grams of p-cyanophenylglyoxal, 60 grams of acetophenone, and 56.5 cc. of acetic anhydride was heated for 2.5 hours in an oil bath at -150 C. "Vacuum was applied to the hot mixture to remove the acetic acid formed, and after standing for 24 hours at room temperature, themixture was triturated with 30 cc. of absolute ethanol, filtered, washed twice with 30 cc. of absolute ethanol, and then 30 cc. of ether. The yellow product thus obtained was recrystallized from 2300 cc. of methanol, yielding 1-benzoyl-2-(p-cyanobenzoyl) ethylene, M. P. 143-145 C. in the form of yellow crystals.

(2) A mixture of 6.7 grams of phenylglyoxal, 7.25 grams of p-cyanoacetophenone, and 7 cc. of acetic anhydride was heated for 2.5 hours in an oil bath at 145-150 C. The reaction mixture was cooled at 4 C. for 24 hours. The mass which formed was filtered, and the product washed with 20 cc. of absolute ethanol. 1-benzoyl-2-(pcyanobenzoyl) ethylene was thus obtained having a M. P. of 141-143 C.

EXAMPLE G 1 -benzoyZ-2- (in-cyanobenzoyl) ethylene (1) A mixture of 65.4 grams of m-cyanophenylglyoxal, 47 cc. of acetic anhydride, and 49.4 grams of acetophenone was heated for 2.5 hours in an oil bath at 145-150 C. Vacuum was applied to the hot mixture to remove the acetic acid formed, and after standing for 48 hours at room temperature, the mixture was triturated with 30 cc. of absolute ethanol, filtered, washed twice with 30 cc. of absolute ethanol, and then 30 cc. of ether. The yellow product thus obtained was recrystallized from 1200 cc. of methanol yielding l-benzoyl 2 (m cyanobenzoyl) ethylene, M. P. 126-127 C., in the form. of yellow plates.

(2) A mixture of 15.2 grams of phenylglyoxal, 16.45 grams of m-cyanoacetophenone and 15 cc. of acetic anhydride was heated for 2.5 hours in an oil bath at 145-150 C. The reaction mixture was allowed to stand .at room temperature for 24 hours. Thesemi-solid mass thus obtained was .triturated with '20 cc. of absolute.ethanol,.fi1tered,

-washed with 15 cc. of absolute ethanol, andair dried. The crudeproductzwas recrystallizedfrom .190 cc. .of absoluteethanol, yielding .1-benzoyl-2- (m-cyanobenzoyl) ethylene, M. P. 126-127 C.

EXAMPLE H Z-phenyZ-5- (m-cyanophenyl) furan A mixture of 100 grams ofstannous chloride dihydrate, 150 cc. of glacial acetic acid and 200 cc. of concentrated hydrochloric acid was refluxed for 5 minutes. To the hotsolution were-added 25 grams (0.096 mole) of l-benzoyl-Z-(m-cyano- .benzoyl) ethylene and the mixture was refluxed for minutes. The mixture was then cooled to 5 C. and theproduct which had solidified on cooling was filtered. The filter cake was sucked dry and then washed with 500 cc. of cold water and air-dried. The crude product was crystallized from 280 cc. of methanol, yielding 2- phenyl-5-(m-cyanophenyl)fural, M. P. 92.5-- 93 'C.

EXAMPLE I Z-phenyZ-S- (p-cyanophenyl) jumn A mixture of 100 grams of stannous chloride dihydrate, 150 cc. of glacial acetic acid and 200 cc. of concentrated hydrochloric acid was refiuxed for 5 minutes. To the hot solution were added grams (0.096 mole) of l-benzoyl-Z-(pcyanobenzoyhethylene and the mixture was refiuxed for 10 minutes. The reaction mixture was cooled to 5 C. and the product which had solidified was filtered. The filter cake was sucked dry and then washed with 500 cc. of cold water and air-dried. The Z-phenyl 5 (p cyanophenyl) furan thus obtained was crystallized from 5'75 cc. of methanol, M. P. 122-124 C.

The following examples will serve to illustrate the preparation of the guanyl, 4,5-dihydro-2- imidazolyl, and dialkylaminoalkylcarbamyl substituted 2,5-diphenyl-chlorofurans and 2,5-diphenyl-furans.

EXANIPLE 1 A solution of 5 grams of LZ-biMp-cyanobenzoyl ethylene in 225 cc. of nitrobenzene was distilled until '75 cc. of distillate had been collected. The solution was cooled to room, temperature and 20 cc. of methanol were added. The slurry was then cooled in an ice bath. for minutes and saturated while stirring with anhydrous hydrogen chloride. The reaction mixture was transferred to a pressure bottle and shaken mechanically for .3 hours at room temperature, during which time a clear dark solution resulted. The sealed bottle was allowed to stand at room temperature for 6 days. The intermediate, 2,5-dilp-W-iminomethoxymethyl) phenyll -3-chloroiuran dihydrochloride began to crystallize after the first day. The amount of precipitate increased and finally, on the sixth day, the heavy orange precipitate was gathered on a filter, washed with anhydrous ether, and dried in a vacuum desiccator. A sample of the intermediate was completely water soluble.

A solution made up of 5.5 grams of 2,5-di[p-(uiminomethoxymethyl) phenyl] -3-chlorofuran dihydrochloride, 50 cc. of methanol; and 1.7 grams of anhydrous ethylene diamine was refluxed for 6 hours. The solution which was originally clear became turbid, and after 2 hours a crystalline precipitate started to appear. The slurry was cooled at 4 C. for 18 hours, filtered, washed with water, andvair dried. inecrystallizedonce from a mixture .of :325-cc. ;of .glacial :acetic .acid, 5-;c.c.

of concentrated -.hydrochloric acid and 3.5 -cc.'.of water, the product obtained was 2,5-bis[p-(4,5- dihydro-2-imidazolyl) phenyl'i 3-chlorofuran dihydrochloride monohydrate, .M. *P. 360 .C. with decomposition. The product was obtained in the .form of .yellow crystals.

.Asuspension of .:2.86.grams-oi 1,2.-bis-( p-cyano- :benzoyliethylene :in :50 .cc. .of :absolute ethanol was stirredgin an .ice .bath:f.or.3.0 minutes, and

- .then .saturated with .dryhydrog-enchloride. The

.slurry was ;stored at room temperature for .24 hours. and then allowed .tozstandfor .7 idayssat room temperature-without stirring, after which time the solid whichhad formed was filtered,

washed with ether, and dried in a vacuunrdesiccator. The solid thus obtained was '2,5-di[p-( riminoethoxymethyl.) phenyl] :3-chlorofuran dihydrochloride.

3.5 grams of .the above .imidic ester :hydrochloride washeated in a pressurebottle at10 .C. for 16 .hours with 60 .cc. of methanolic ammonia. The .reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was boiled with :60 :cc'. of glacial :acetic acid, .5 .cc. :of concentrated hydrochloric acid, .and .3 cc. .of water, filtered from :the insoluble ,matter, andcooled slightly. .Ether was :added until the filtratebecame slightly turbid,

the solution being then cooled :to room temperature, and .tfinally stored iat4 .C. for 16 ,hours. The product was collected :on :afilter, washed with ether, and :dried. Upon recrystallization ,from acetic acid-watereether, .2,5+bis(p-guanylphenyl') -3-chlorofuran .dihydrochloride monohydrate,.M. vP. 338-1339 0., with decomposition, was obtained.

EXAMPLE 3' A suspension of 11.4 grams of 1, 2-bis(m-cyanobenzoyDethylene in 200 cc. anhydrous ethanol -was:stirre'd while cooling in an .ice :bathfor 30 minutes. The .cold mixture was saturated with anhydrous hydrogen chloride, .and then stirred at room temperature for 24 :hours. The mixture was allowed .to .stand for 5 days .atroom temperature without stirring, :and then after .dilution with 200.00. of ether, vthe solid'was gathered on :a fiilter, washed with .ether, and dried 'invacuo over solid potassiumxhydroxide for several days.

The solid was 2,5-di[mstmiminoethoxymethyl) phenyl] 3-chlorofuran ;dihydrochloride.

The above obtained 'imidi'c ester hydrochloride was heated at C. in .a pressure bottle :for -6 hours with 200- cc. of .11 per cent methanolic ammonia. .After being :cooled to room temperature, the clearsolution was evaporated to dryness in vacuo. The .solid was dissolved in 300 cc..of

hot glacial acetic acid and "60 cc. of water.- The solution was-clarified by filtration through a 'hot methanol-water, the pure base was obtained in the form of very pale yellow crystals, M. P. 186188 C., with decomposition.

EXAMPLE 4 Starting with 5.7 grams of l-(m-cyanobenzoyl) -2- (p-cyanobenzoyl) ethylene, and following the same procedure as described in Example 3, there was obtained 2-[m-(a-iminoethoxymethyl) phenyl] [p-(a-iminoethoxymethyl) phenyll-3(or 4) -chlorofuran dihydroohloride. The imidic ester hydrochloride was heated at 70 C. for 6 hours in a pressure bottle with 130 cc. of 11 per cent methanolic ammonia. The reaction mixture was cooled to room temperature, and the crystalline product was filtered, washed with ether, and dried, yielding 2-(mguanylphenyl) 3(or 4) chloro 5 -(p guanylphenyDfuran dihydrochloride monohydrate, M. P. 348-350" C.

EXAMPLE 5 Starting with 5.7 grams of l-(m-cyanobenzoyl) -2- (p-cyanobenzoyl) ethylene, and proceeding in the same manner as described in Example 3, there was obtained 2-[m-(a-iminoethoxymethyl) phenyll 5 [p (a iminoethoxymethyl) phenyl] -3 (or 4) -chlorofuran dihydrochloride. The imidic ester hydrochloride was refluxed for 6 hours with 50 cc. of methanol and 2.44grams of anhydrous ethylene diamine. The clear solution became turbid after 4 hours and at the end of 6 hours a very heavy slurry of crystals had formed. After cooling for 16 hours at 4 C., the solid was gathered on a filter, Washed with ether, and dried. Recrystallized from 450 cc. of glacial acetic acid, 60 cc. of water, and 110 cc. of ether, the 2-[m-(4,5 dihydro 2 imidazolyl) phenyll 3 (or 4) -chloro-5- [p- (4,5-dihydro-2-imidazolyl) phenyll -furan hydrochloride was obtained in'the form of yellow crystals, M. P. 336-338 C. with decomposition.

EXAMPLE 6 A suspension of 10.5 grams of l-benzoyl-Z-(mcyanobenzoyl) ethylene in 50 cc. of absolute ether, and 50 cc. of methanol was stirred while being cooled in an ice bath for 30 minutes. Dry hydrogen chloride was passed into the suspension for 25 minutes. Within the first 5 minutes, the suspended matter dissolved and the solution became progressively darker as the hydrogen chloride wasadded. The solution was transferred to a pressure bottle. Within minutes, a heavy crystalline precipitate formed. After standing at room temperature for 24 hours, the slurry was diluted with ether, the crystalline precipitate was filtered, washed with ether, and dried in vacuo over solid potassium hydroxide, yielding 2-pheny1-3 (or 4) -chloro-5- [m- (a-iIIllIlO- methoxymethyl) phenyll -furan hydrochloride, in the form of yellow-orange crystals which, on recrystallization from methanol-ether, meltedflat A solution of 5.9 grams of the thus obtained imidic ester hydrochloride in cc. of methanol containing 1.35 grams of anhydrous ethylene diamine was refluxed for 6 hours. The solution was cooled at 4 C. for about 16 hours, and the resulting crystalline product was filtered, washed with ether, and then recrystallized from 140 cc. of absolute ethanol, 15 cc. of alcoholic hydrogen chloride, and 9 cc. of water to yield 2-phenyl-3(or 4) -ch-loro-5-[m (4,5 dihydro 2 imidazolyl) phenyll-furan hydrochloride, 287-288". C.,

in the form of pale yellow crystals. The free base of this compound was prepared by neutralizing a methanol-water solution of the hydrochloride with dilute sodium hydroxide solution. Recrystallized from methanol, the free base melted at 188.5-189.5 C.

EXALEPLE 7 A solution of 5.6 grams of 2-phenyl-3(or 4)- chloro 5 [m (a. iminomethoxymethyl)- phenyll-furan hydrochloride in 100 cc. of 11 per cent methanolic ammonia was heated in a pressure bottle at C. for 6 hours. The clear solution was cooled to room temperature and evaporated to dryness in vacuo. The residue was recrystallized with a mixture of 250 cc. of acetonitrile, 3 cc. of concentrated hydrochloric acid, and 20 cc. of water, yielding 2-phenyl-3(or 4)- chloro-5- (m-guanylphenyl) furan hydrochloride, M. P. 250-253 C. in the form of pale yellow crystals.

EXAMPLE 8 A stirred suspension of 5.22 grams of l-benzoyl-2-(p-cyanobenzoyl)ethylene in 50 cc. of methanol was cooled in an ice bath for 30 minutes. A moderate stream of anhydrous hydrogen chloride was passed into the stirred suspension. Within 5 minutes, all the suspended matter had dissolved. The introduction of the hydrogen chloride was continued for a total of 15 minutes, and the solution become progressively darker.

The solution was transferred to a pressure bottle and allowed to stand at room temperature for 2 days. Crystallization began within 30 minutes after the solution'was transferred to the pressure bottle. The solid was gathered on a filter, washed with ether, and dried in vacuo over solid KOl-I, yielding 2-phenyl-3(or 4) -ch1oro-5- [p- (a-iminomethoxymethyl) phenyll furan hydrochloride, M. P. 230235 C'.

5.4 grams of the imidic ester hydrochloride thus obtained was refluxed for 6 hours with 45 cc. of methanol, and 1.35 grams of anhydrous ethylene diamine. The reaction mixture was cooled at 4 C. and a crystalline base, M. P. 186- 203 C., was obtained. Concentration of the mother liquor to 20 cc. followed by cooling at 4 C. produced a second crop of crystals of the corresponding hydrochloride, M. P. 270-288 C. with decomposition. The two materials were combined and heated on a steam bath with cc. of methanol and 5 ,cc. of methanolic hydrogen chloride. A small amount of white insoluble matter was removed by filtration, and the filtrate was cooled to 4 0., whereupon crystals formed in the form of yellow cubes and light yellow needles. This material was recrystallized from a mixture of cc. of acetonitrile, 5 cc. of concentrated hydrochloric acid, and 30 cc. of water, whereupon fiufiy greenish yellow needles, M. P. 3G53o9" C. with decomposition, were obtained. The 2-phenyl-3(0r 4)-chloro-5-[p- (4,5-dihydro-2-imidazolyl) phenyl] -furan hydrochloride thus obtained was found to crystallize ,C., and was obtained in the form of pale yellow crystals.

9 EXAMPLE 9 A solution of' 5.7 grams (0.023 mole). of 2- phenyl--(m-cyanophenyl)furan in 25' cc. of chloroform and. 1.2 cc. (0.03 mole) of methanol was cooled in an ice bath for 30. minutes. Ane hydrous hydrogen chloride was passed into the cold solution for 7 minutes and the resulting dark-colored saturated solutionv was stored at about 4 C. for about 16 hours. The reaction mixturev which now consisted of a thick slurry of orange crystals was heated in vacuo to 50 C. in order to remove the chloroform. The residue was triturated with 125 cc. of ether and the solid was filtered with suction. The. filter cake was Washed three times-with 75 cc. portions of. ether. The resulting compound was 2-phenyl.-5-[m.-(a-. iminomethoxymethyl) phenyl] -furan. hydrochloride.

A mixture of 3.2 grams (0.01 mole). of 2'- phenyl-5- [ma-iminomethoxymethyl) phenyl-lfuran hydrochloride, 2000 of ethanol and 0.78 cc.. (0.012 mole) of anhydrous ethylene diamine was refluxed for six hours. The clear solution was allowed to crystallize at about 4 C. A first crop of crystals having a M. P. of 274-276 C. was obtained. The mother liquor was evaporated to dryness and crystallization of the residue from cc. of methanol yielded a second crop of crystals, M. P. 272-274 C. The two crops were combined and recrystallized from 35 cc. of methanol containing 1 cc. of per cent methanolic hydrogen chloride. The crystals were 2-phenyl-5- [m- (4,5-dihydro-2-imidazolyl) phenyl] -furan hydrochloride, M. P. 276-278 C. 1

A methanol-water solution of 2-phe1iyl-5- [m (4,5 dihydro-2-imidazolyl)phenyl] -furan hydrochloride was converted to the free base with an excess of sodium hydroxide solution. Recrystallized from methanol, the white crystalline 2 phenyl 5 [m (4,5 dihydro 2- imidazolyDphenyll-furan melted at l80-l81 C. To 100 mg. of the free base dissolved in 3 cc. of methanol were added 3 drops of 85 per cent lactic acid. The solution was evaporated to dryness in vacuo and the residue was crystallized, first from ethanol-ether and then from acetonitrile. The lactate salt thus obtained melted at 158-160 C.

EXAIVIPLE 10 A mixture of 7.75 grams (0.025 mole) of 2- phenyl 5 [m (a iminomethoxymethyD- phenyl] -furan hydrochloride and 150 cc. of 11 per cent methanolic ammonia was heated in a pressure bottle for six hours at 70 C. The solution was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was dissolved in a hot mixture of 100 cc. of acetonitrile and 10 cc. of water. The solution was cooled to about 4 C. and a total of 200 cc. of ether in 50 cc. portions was added over a period of seven hours. 2-phenyl-5-(m-guanylphenyDfuranhydrochloride crystallized in the form of buiT-colored needles and melted at 215- 216 C.

EXAMPLE 1 1 A solution of 38 grams (0.155 mole) of 2-pheny1-5-(p-cyanophenyl)furan in 200 cc. of chloroform and 9.5 cc. (0.24 mole) of methanol was cooled in an ice bath for minutes. Anhydrous hydrogen chloride was passed into the cold solution for 10 minutes and a resulting dark-colored saturated solution was stored at about 4 C. for about 16 hours. The reaction mixture was heated in. vacuo at about-50. C. in order to remove thechloroform. The SOIidT residue was: triturated with500 cc. of ether and the. solid wasfiltered off with suction. The filter cake was washed with a total of 500 cc; ofiether'and'air-dried. The cakewith 2500. of cold ethanol and then 100 cc. of

ether. Recrystallized from 700 cc. of methanol containing 25' cc. of 25per cent methanolic hydrogen chloride, the 2-phenyl-5-[p-4',5-dihydro- Z-imi'dazolyDphenyll-furan hydrochloride thusobtained melted at 312-313 C. with decomposition.

- A methanol-water solution of 2-ph'enyl-5-[p- (4,5-dihydro-2-imidazolyl) phenyl] -furan hydrochloride was converted to the free base by treatment with an excess of sodium hydroxide solution. Recrystallized from methanol, the crystalline free base, 2-phenyl-5- [p-(4,5-dihydro-2- imidazolyl)phenyl]-furan, melted at 203-204 C.

To a solution of 1.3 grams of' 2-phenyl-5-[p (4,5dihydro-2-imidazolyl)" phenyl]-furan dissolved in 15' cc. of warm methanol was added 0.55 cc. of per cent lactic acid. The solution was evaporated to dryness invacuo and the solid residue was recrystallized from 15 cc..of methanol and '10 cc. of ether. 2-phenyl-5-[p- (4,5-dihydro--' Z-imi'dazol'yl)phenyll-furan lactate was obtained in the form of pale yellow crystals, M. P.

EXAMPLE 12 A. mixture of. 12.4.grams (0.04 mole) of 2-phenyl.-5- [p- (a-iminomethoxymethyl) phenyl] furan hydrochloride and 150 cc. of 11 per cent methanolic. ammonia. was heated. in a pressure bottlev EXAMPLE 13 1 gram of 2-phenyl-5-lp-(a-iminomethoxy methyl) phenyl]-furan hydrochloride was. refluxed forone hour with cc. of water. The mixture was. cooled to 25 C. and the crude solid product was filtered, washed with water and airdried. On recrystallization. from 75 cc. of meth anol, there was obtained 2-phenyl-5-(p-carbomethoxyphenyDfuran, M. P. 153-155 C. I

A mixture of 7.87 grams (0.023 mole) of 2-phenyl-5- (p carbomethoxyphenyl) furan and 85 cc. of fi-diethylaminoethylamine was refluxed for 16 hours. The excess amine was removed in vacuo and the viscous residual oil was placed in a vacuum desiccator over sulfuric acid. After several days some crystallization began and eventuallythe entire residue became a mass of needles interspersed through the oil. The entire mass was dissolved in 50 cc. of hot acetonitrile, cooled slightly, and set in a refrigerator. After three weeks a mass of crystals had appeared. The supernatant liquid was decanted and the solid The residue was crystallized.

11 was washed with ether. The 2'-phenyl-5-[p-(p-. diethylaminoethyl) carbamylphenyll furan thus obtained was recrystallized from 10 cc. of acetonitrile, M. P. 106-107" C. The hydrochloride was prepared by dissolving the base in an equivalent amount of dilute hydrochloric acid.

In a similar manner 2-phenyl-5-[m-(fi-diethylaminoethyl) carbamylphenyll -furan may be prepared from 2-phenyl-5-(m-carbomethoxyphenyl) -furan which in turn can be prepared by refluxing with water 2-phenyl-5[m-(a-iminomethoxymethyl) phenyl] -furan hydrochloride.

EXAMPLE 14 A mixture of 10.62 grams (0.03 mole) of 2-phenyl-3(or 4)-chloro-5-[m-(a iminom'ethoxymethyDphenyll-furan hydrochloride and 600 cc. of water was refluxed for 3.5 hours. The reaction mixture was cooled in an ice bath, the supernatant liquid was separated by decantation, and the residue was dissolved in 300 cc. of hot methanol. The solution was cooled first to room temperature and then at about 4 C. whereupon crystallization of 2-phenyl-3(or 4) -chloro-5-(mcarbomethoxyphenyDfuran occurred, M. P. 109-111 C.

A solution of 1.3 grams (0.0041 mole) of 2-phenyl-3(or 4) -chloro-5-(m carbomethoxyphenyl) furan in 50 cc. of methanol and 25 cc. of 1.0 N sodium hydroxide was refluxed for three hours. The hydrolysis mixture was diluted with 250 cc. of cold water and acidified to Congo-Red with 6 N hydrochloric acid. The resulting precipitate was filtered, washed with water and dried in vacuo at 70 C. The 2-phenyl-3(or 4) -chloro- 5-(m-carboxyphenyl)furan thus obtained was purified by sublimation at 220 C. and 1.0 mm., followed by recrystallization with benzene-ethyl acetate, M. P. 223-224 C.

Six and two-tenths grams (0.021 mole) of crude 2-phenyl-3 (or 4) -ch1oro-5- (m-carboxyphenyDfuran was suspended in 75 cc. of thionyl chloride. The mixture was refluxed for 15 minutes and then the clear solution was allowed to stand at room temperature for about 16 hours.

The solvent was then removed leaving a residue which was recrystallized from ether-petroleum ether to yield crystals of 2-phenyl-3(or 4)- chloro-5-(m-chloroformylphenyl)furan, M. P. 111-'113 C.

To 0.9 gram (0.0077 mole) of B-diethylaminoethylamine, 50 cc. of water and 2 cc. of 1 N sodium hydroxide contained in a flask cooled withan ice bath, was added with stirring over 15 minutes a solution of 0.5 gram (0.0016 mole) of 2-phenyl-3(or 4) -chloro 5 (m chloroformylphenyl) furan in 35 cc. of ether. The mixture was stirred 45 minutes longer while being cooled in the ice bath and finally the ether layer was separated. The aqueous phase was extracted with 25 cc. of ether and the combined ether extracts were dried at 4 C. over sodium'sulfate. Removal of the solvent in vacuo left an oil which was converted to the hydrochloride with methanolic hydrogen chloride. The amorphous hydrochloride was crystallized from methanol, benzene and ether to yield 2-phenyl-3(or 4) -chloro-5-[m- (fidiethylaminoethyl)carbamyl phenyll-furan hydrochloride, M. P. 159-161 C.

The same compound can be prepared in the following manner:

A mixture of 5.0 grams (0.016 mole) of 2- phenyl-3(or 4)-chloro 5 (m carbomethoxyphenyDfuran and cc. of p-diethylaminoethylamine was refluxed for 12 hours. The excess amine was removed in vacuo and the residual oil was converted to the hydrochloride with meth-. anolic hydrogen chloride. Removal of the so1- vent left the resinous hydrochloride, which was dissolved in 20 cc. methanol and 50 cc. of ben- 'zene. Ether was added to slight turbidity and the solution was then kept at about 4 C. .for 16 hours. Crystallization of 2-phenyl-3 (or 4) chloro-5-[m (13 diethylaminoethyl)carbamyl phenyl] -furan hydrochloride occurred. The compound had a melting point, on recrystallization from methanol-benzene-ether, of 157-159 C.

We claim:

1. A compound of the class consisting of 2,5 diphenyl-furans and 2,5-diphenyl-monochloro furans wherein at least one of the phenyls has attached thereto a member of the group consisting of guanyl, and dialkylaminoalkylcarbamyl radicals, and the acid addition salts thereof.

2. 2,5-diphenyl-furans wherein at least one at the phenyls is substituted by the radical 3. 2,5-diphenyl-monochlorofurans wherein at least one of the phenyls is substituted by the radical 4. 2,5-diphenyl-furans wherein at least one of the phenyls is substituted by the radical alkyl C O NH-alkyleneN alkyl 5. 2,5-bis(m guanylphenyl)monochlorofuran dihyrochloride. I

6. Z-phenyl 5 [p (19 diethylaminoethyl) carbamylphenyllfuran.

- MOSES WOLF GOLDBERG. ALBERT ISRAEL RACHLIN.

No references cited. 

1. A COMPOUND OF THE CLASS CONSISTING OF 2,5DIPHENYL-FURANS AND 2,5-DIPHENYL-MONOCHLOROFURANS WHEREIN AT LEAST ONE OF THE PHENYLS HAS ATTACHED THERETO A MEMBER OF THE GROUP CONSISTING OF GUANYL, AND DIALKYLAMINOALKYCARBONYL RADICALS, AND THE ACID ADDITION SALTS THEREOF. 